Cancer is the second leading cause of death in the United States, exceeded only by heart disease. Current pharmacological treatments for cancer utilize a toxic dose of a compound that is administered in a precise dosing range to preferentially destroy the cancerous cells (chemotherapy), and minimize damage to healthy tissue. Despite efforts to focus the toxic effects on the cancerous tissues, severe or even life-threatening adverse effects may occur, such as serious disorders of the blood, gastrointestinal tract, liver, kidneys, and other organs. Most current anticancer drugs thus have a narrow therapeutic window: the range between the therapeutic dose and the maximum tolerated dose is very small. Due to this toxicity, as well as the fact that most anticancer drugs are administered intravenously, nearly all cancer chemotherapy must be administered in a hospital or clinic. An additional problem with most current cancer chemotherapy is that cancers frequently develop resistance to the drugs, so that recurrence of disease is common.
It is a goal of cancer researchers to discover efficacious anticancer agents while avoiding the adverse effects of chemotherapy treatments. Epidemiology offers some clues in this regard, and has led to the discovery of safe anticancer agents. By examining the practices of cultures exhibiting a lower incidence of cancer and investigating the possible sources of the decreased incidence of disease, researchers may be able to discover that the food or drink consumed by the people of that culture contains compounds that have anticancer properties. These dietary compounds possessing anticancer properties can then be modified to enhance their anticancer effects while retaining their safety. Of particular interest in this regard are certain polyphenols that occur in green tea.
Specifically, compounds such as the catechins, (−)-epigallocatechin-3-gallate (EGCG), (−)-epigallocatechin (EGC), (−)-epicatechin-3-gallate (ECG), and (−)-epicatechin (EC) have been implicated in cancer chemoprevention. Both EGCG and EGC exhibit substantial anticancer activity (EGCG is particularly potent), with ECG and EC somewhat less active.

Researchers studying these naturally occurring polyphenols have determined that EGCG is not only the most abundant of the above catechins, but also the most potent chemopreventive component in green tea. A large number of in vitro and in vivo studies have shown EGCG to possess a wide variety of anticancer activities. In animal studies, orally administered EGCG and related green tea polyphenols have shown efficacy in preventing and treating cancers of the lung, breast, liver, skin, esophagus, stomach, duodenum, pancreas, and colon (Hirosi et al. (1997) Cancer Lett. 112:141–147). As an antioxidant, EGCG exerts antimutagenic and chemoprotective effects through neutralization of free radicals, protection of DNA from strand breaks and other damage caused by reactive oxygen species (Anderson et al. (2001) Carcinogenesis 22:1189–1193), and inhibition of oxidation of some carcinogenic substrates of human cytochrome P450 (Muto et al. (2001) Mutat. Res. 479:197–202). In general, EGCG inhibits the metabolic activation of procarcinogens by cytochrome P450, which represents a significant chemoprotective activity against carcinogenesis (ibid).
Another proposed anticancer activity of EGCG involves the induction of apoptosis. One mechanism of apoptosis appears to be binding of EGCG to Fas on the cell surface, which triggers Fas-mediated apoptosis (Hayakawa et al. (2001) Biochem. Biophys. Res. Commun. 285:1102–1106). Other researchers have suggested that normal cells are not affected by the apoptotic effects of green tea polyphenols because EGCG and other constituents of green tea cause the induction of p57, which acts to inhibit apoptosis in untransformed cells (Hsu et al. (2001) Anticancer Res. 21(6A):3743–3748).
Other anticancer mechanisms include, without limitation: inhibition of topoisomerases I and II (Suzuki et al. (2001) Biol. Pharm. Bull. 24:1088–1090); inhibition of nuclear factor kappa-B (NFκB), possibly through inhibition of the IκB kinase complex (Yang et al. (2001) Mol. Pharmacol. 60:528–533), which results in the suppression of NO synthesis and subsequent generation of carcinogenic nitrites; scavenging of carcinogenic nitrites (Pannala et al. (1997) Biochem. Biophys. Res. Commun. 232:164–168); inhibition of matrix metalloproteinases involved in tumor metastasis (Isemura et al. (2000) Biofactors 13:81–85; Demeule et al. (2000), Biochim. Biophys. Acta 1478:51–60); inhibition of the androgen receptor in prostate cancer (Ren et al. (2000) Oncogene 19:1924–1932); inhibition of cellular hyperproliferation induced by overexpression of epidermal growth factor receptor (Liang et al. (1997) J. Cell Biochem. 67:55–65); and inhibition of angiogenesis, at least in part by suppressing the induction of vascular endothelial growth factor (VEGF) (Jung et al. (2001) Br. J. Cancer 84:844–850).
EGCG can be obtained as the natural product (see, e.g., U.S. Pat. No. 6,210,679 to Bailey et al.) or chemically synthesized using an enantioselective synthesis recently developed at SRI International (Menlo Park, Calif.); see Zaveri (2001) Organic Letters 3(6):843–846. However, EGCG per se is not a viable candidate for use as a therapeutic agent because it is only minimally bioavailable when administered orally, and in addition, EGCG is extensively conjugated by action of the liver. Because of the poor absorption when given orally, one would have to drink at least 8–10 cups of green tea a day to gain its chemopreventive benefit (EGCG is present in green tea at a concentration of about 200 mg per brewed cup; see Mukhtar et al. (1999) Toxicol. Sci. 52 (suppl.):111–117). Furthermore, green tea contains 70 mg of caffeine per cup, so drinking enough for chemoprevention would result in caffeine-related side effects. These are being observed in the ongoing clinical trials of green tea.
Several researchers have attempted to synthesize analogs of EGCG that overcome the aforementioned limitations inherent in EGCG itself. For example, it is not yet known which of the enantiomers of EGCG is responsible for the anticancer activity of this compound. An enantioselective synthesis of EGCG was devised involving synthesizing the three aromatic fragments separately, and then assembling them in a stereoselective fashion (Li and Chan (2001) Organic Letters 3(5):739–741). These authors however did not report any results regarding the relative efficacy of either enantiomer. Zaveri (2001), supra, describes synthesis of a 3,4,5-trimethoxybenzoyl ester analogue of EGCG and the 2α,3β enantiomer thereof. Although both compounds described by Zaveri were found to inhibit the growth of breast cancer cell lines in vitro, the potency of these compounds was somewhat less than that of EGCG itself.
Accordingly, there is a need for synthetic strategies for generating analogs of EGCG and other green tea polyphenols, in order to optimize the chemopreventive and chemotherapeutic effects of these compounds. The present invention is the result of extensive, systematic research to design novel flavanoids related to EGCG, but optimized to enhance their anticancer activity and retain a low toxicity.